Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Br-].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Zn+])=[CH:20][CH:19]=1)#[N:17]>O1CCCC1.ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[O:6][C:5]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(C[Zn+])cc1
Reactant: N#Cc1ccc(-c2ccc(Br)o2)nc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2ccc(-c3ccc(C#N)cn3)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
Continuing with Scheme 7, a solution of 2 (996 mg, 4 mmol) in tetrahydrofuran (25 mL) was added palladium tetrakis(triphenyl-phosphine) (228 mg) and p-cyanobenzyl zinc bromide (12 mL, 0.5 M in THF, 6 mmol). The reaction mixture was stirred 24 h at room temperature. The mixture was diluted with dichloromethane, washed with saturated NH4Cl and the organic layer was dried over anhydrous Na2SO4. After filtration and on concentration the residue was purified by chromatography (SiO2), hexanes (100–40%)/EtOAc (0–60%), to afford 35 in 48% yield, mp 204–206° C. 1H nmr (DMSO-d6); δ 4.23 (s, 2H), 6.46 (d, J=3.3 Hz, 1H), 7.27 (d, J=3.3 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.4 Hz, 1.8 Hz, 1H), 8.92 (d, J=1.8 Hz, 1H). 13C nmr; δ 156.3, 152.6, 150.9, 150.6, 143.2, 140.5, 132.4, 129.6, 118.6, 117.5, 117.1, 113.5, 110.3, 109.5, 106.0, 33.5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:25]C1C=CC=CC=1S(Cl)(=O)=O.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](NC1C=C(N2CCN(C(OC(C)(C)C)=O)CC2)C2OC=CC=2C=1)(=[O:45])=[O:44]>>[ClH:25].[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43]([NH:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCN(CC)C(=O)CN1CCN(c2cc(N)cc3ccoc23)CC1
Product: CCN(CC)C(=O)CN1CCN(c2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CC1
Product: Cl
Reaction time: 0.05 h

Procedure:
2-[4-(5-Amino-1-benzofuran-7-yl)piperazin-1-yl]-N,N-diethylacetamide (0.095 g, 0.29 mmol; Intermediate 23) was reacted with 2-chlorobenzenesulfonyl chloride according to the procedure of Intermediate 19. Yield: 0.06 g (41%) after purification by preparative HPLC (System E; 20-50% MeCN). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (t, J=6.9 Hz, 3H) 1.15 (t, J=6.9 Hz, 3H) 3.09-3.43 (m, 7H) 3.55-3.65 (m, 2H) 3.67-3.76 (m, 2H) 4.39 (s, 2H) 6.62 (d, J=1.0 Hz, 1H) 6.86 (d, J=1.3 Hz, 1H) 6.93 (d, J=1.5 Hz, 1H) 7.47 (t, J=7.0 Hz, 1H) 7.60 (q, J=7.7 Hz, 2H) 7.91 (d, J=1.3 Hz, 1H) 8.01 (d, J=7.8 Hz, 1H) 10.08 (s, 1H) 10.46 (s, 1H). HPLC purity 92%, RT=1.85 min (System A; 10-97% MeCN over 3 min). MS (ESI+) m/z 505.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30](OCC)([O:34]CC)[O:31][CH2:32][CH3:33].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30]([O:31][CH2:32][CH3:33])=[O:34]
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (375 mg, 0.677 mmol) in acetone (8 mL) and water (2 mL) was added p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol). The reaction mixture was stirred at room temperature for 2 hours, then quenched with ice water. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, then concentrated in vacuo to remove the majority of the acetone. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (29:1 dichloromethane:methanol) provided ethyl 7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-6-carboxylate (175 mg, 54%) as a brown solid. Rf 0.08 (29:1 dichloromethane:methanol); 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.09 (d, 1H), 7.82 (d, 1H), 7.65 (m, 2H), 7.14 (t, 2H), 6.30 (d, 1H), 5.19 (d, 1H), 4.46 (q, 2H), 4.32 (m, 1H), 2.06 (m, 2H), 1.77–1.21 (m, 9H); MS m/z 480 (M+1).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:29]1[N:30]=[C:31]([NH:34]C(=O)CCl)[S:32][CH:33]=1)[C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH:16]([S:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH3:17])[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].[Na+].NC(N)=S.Cl>O>[CH2:1]([O:3][N:4]=[C:5]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH:16]([S:18][C:19]3[NH:20][N:21]=[N:22][N:23]=3)[CH3:17])[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: NC(N)=S
Agent: [Na+]
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
To a solution of 3.90 g of sodium 7β-{α-ethoxyimino-[2-(chloroacetamido)thiazol-4-yl]acetamido}-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate in 50 ml of water is added 1.52 g of thiourea. The mixture is stirred at room temperature for 3 hours and adjusted to pH 2.0 with 1N hydrochloric acid. The resulting precipitates are filtered, washed with water and dried to obtain 2.40 g of 7β-[α-ethoxyimino-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. Yield 73.1%.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH2:11]O)=[C:9]([Cl:13])[N:8]=[N:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:22]>C(Cl)Cl>[ClH:13].[CH2:1]([C:5]1[C:10]([CH2:11][Cl:22])=[C:9]([Cl:13])[N:8]=[N:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1c(-c2ccccc2)nnc(Cl)c1CO
Solvent: ClCCl
Product: CCCCc1c(-c2ccccc2)nnc(Cl)c1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-butyl-6-chloro-5-hydroxymethyl-3-phenyl-pyridazine (0.32 g, 1.16 mmol) in CH2Cl2 (5 mL) is added SOCl2 (2 mL). The resulting clear solution is stirred at room temperature for 3 hours. The solvent is removed in vacuo and the residue is dissolved in toluene (5 mL) and evaporated to remove the remaining SOCl2. The resulting semi-solid is used directly for the next step. LC-MS (M+1) 295.
Reaction SMILES: CC(=C[CH2:5][CH2:6][CH:7]([CH3:22])[CH2:8][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH3:22][CH:7]1[CH2:6][CH2:5][CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:21])[CH2:8]1
Reactant: C=CCCCCCCCCCC(=O)CC(C)CCC=C(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CC1CCC=CCCCCCCCCCC(=O)C1
Yield: 48.4 %

Procedure:
Grubbs' Catalyst, 2nd generation (benzylidene [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene] dichloro (tricyclohexylphosphine) ruthenium) (560 mg, 0.066 mmol, 2 mol %), was added to a solution of 2,6-dimethyl-nonadeca-2,18-dien-8-one (1 g, 3.3 mmol, prepared as above in Example IV) in dichloromethane at room temperature. The reaction mixture was stirred at reflux for 12 hours. The reaction mixtures was subsequently concentrated and then chromatographed on silica with ethyl acetate in hexanes (2%) as the eluent providing 3-methyl-cyclohexadec-6-enone as a colorless oil (0.4 g). This oil was then filtered through a slurry of silica gel/activated charcoal.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].Cl.[NH:6]1[CH:10]=[C:9]([CH2:11][C:12]([OH:14])=O)[N:8]=[CH:7]1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[OH:14][C:12]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1
Reactant: OP(O)O
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(O)(Cc1c[nH]cn1)P(=O)(O)O
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
3 g. Phosphorous acid are added to 3.5 g. imidazol4-ylacetic acid hydrochloride (m.p. 198-200° C.) in 40 ml. chlorobenzene. The reaction mixture is stirred for 10 minutes at 110° C., cooled and 9 g. phosphorus trichloride slowly added dropwise thereto. The reaction mixture is heated for 16 hours to 110° C., cooled, the chlorobenzene is decanted off from an orange-coloured syrup and the residue is mixed with 50 ml. 6N hydrochloric acid. The suspension is heated under reflux for 5 hours, cooled, mixed with charcoal and filtered off with suction. The filtrate is evaporated, dried and boiled up with acetone for 2 hours. The residue (4.3 g.) is dissolved in water, the solution is adjusted with 2N aqueous sodium hydroxide solution to a pH of 5, mixed with methanol and the precipitate obtained is filtered off with suction. There are obtained 1.2 g. (about 16.9% of theory) of the desired product; m.p.>290° C. The compound is obtained as the monosodium salt containing 2 moles of water of crystallisation (Mrel =0.37).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[NH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NN4CCCCC4)c(F)c3)c2cc1OC
Yield: 61.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (43 mg, yield 61%)
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Li]CCCC.[F:10][CH:11]([F:31])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=[O:26])=[O:21])=[CH:15][CH:14]=1>C1COCC1.COCCOC>[F:10][CH:11]([F:31])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[C:20]([C:22]2[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]([OH:26])[C:3]#[C:2][CH2:1][OH:4])[CH:23]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: O=Cc1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Reactant: C#CCO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C(C(=O)c1cccc(C(O)C#CCO)c1)c1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A stirred solution of propargyl alcohol (0.1 g, 1.78 mmol) in dry THF at −78° C. under nitrogen was treated dropwise with 1.9 M n-BuLi (1.88 mL, 3.57 mmol) over 10 min, stirred for 0.5 h and warmed to 0° C. A 3 mL portion of this solution was added to a stirred solution of 3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]benzaldehyde (0.15 g, 0.49 mmol) in dry DME at 0° C. under nitrogen. After 10 min, the reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (30% to 70% ethyl acetate/petroleum ether) gave 1-[4-(difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1,2-dione as a clear oil, 52 mg (29% yield). Using essentially the same procedure described in Example 1, step c, and employing 1-[4-(difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1,2-dione (0.052 g, 0.14 mmol), the title compound was obtained as a slight brown foam, 0.031 g (52% yield), identified by NMR and mass spectral analyses. MS (ES+): 416 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:7][C:8]=1[F:9].CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH3:33])=[O:31])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COC(=O)C1CCNC(c2ccc(F)c(F)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
Methyl 2-(3,4-difluorophenyl)piperidine-4-carboxylate hydrochloride (6.1 g, 20.91 mmol) and DIPEA (9.13 mL, 52.28 mmol) were dissolved in DCM (30 mL). Methyl chloroformate (1.944 mL, 25.09 mmol) was added and the reaction stirred at room temperature for 1.5 h. DCM (170 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo yielding dimethyl 2-(3,4-difluorophenyl)piperidine-1,4-dicarboxylate (6.58 g, 100%) as a dark oil. MS m/z 314 (M+H)+.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCCOCOCCCCCCCCCC(O)=O.[CH:45]1([N:51]=[C:52]=[N:53][CH:54]2[CH2:59][CH2:58][CH2:57]CC2)CCCCC1>O1CCCC1>[CH3:1][N:51]([C:52]1[CH:57]=[CH:58][CH:59]=[CH:54][N:53]=1)[CH3:45]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: COCCOCOCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 758 mg of 10-(methoxyethoxymethoxy)decanoic acid, 6 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 829 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[N:21]1([C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[O:10][C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29])[CH2:26][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A solution of 2-chloro-4-morpholin-4-yl-furo[3,2-d]pyrimidine-6-carbaldehyde (300 mg, 1.12 mmol) and 2-piperazin-1-ylisobutyramide dihydrochloride (327 mg, 1.33 mmol) in DCE (12 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (358 mg, 1.69 mmol) was added and the mixture stirred for 6 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 90:10) to afford the title compound as a tan solid (390 mg, 82%). LCMS (Method H): RT=2.39 min, M+H+=423
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([Cl:14])[CH:12]=[CH2:13]>C(OCC)(=O)C>[Cl-:14].[CH2:11]([N+:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:10])[CH3:1])[CH:12]=[CH2:13]
Reactant: C=CCCl
Reactant: CN(C)Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC[N+](C)(C)Cc1ccccc1
Product: [Cl-]
Reaction time: 168 h

Procedure:
27 grams of dimethylbenzyl amine was added to 15.4 grams of allyl chloride in 42.4 grams of ethyl acetate. The reaction was endothermic, with a crystalline product forming within 5 minutes. After 7 days standing at 25° C., the white solid was filtered, washed, and dried. The chloride content of the quaternary halide was 95.5% of theoretical.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([S:15][C:2]2[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: Clc1ncc(Br)cn1
Product: Brc1cnc(Sc2ccccc2)nc1

Procedure:
The title compound was prepared from 2-chloro-5-bromo-pyrimidine and thiophenol as described in Example 1; yield: 90% of a non-crystalline product which was pure enough for the successive oxidation. MS m/e: 267 (M, 100%). 1H NMR (CDCl3): δ7.4 (Ph), 8.50 (H-4, H-6).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[CH3:8])=O.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:17]2[C:6](=[O:9])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3]2=[O:5])=[CH:14][CH:13]=1
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: COc1ccc(CN)cc1
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2=O)cc1

Procedure:
2,3-Dimethylmaleic anhydride (1 g, 7.9 mmol) and 4-methoxybenzylamine (1 mL, 7.9 mmol) were heated to reflux in 5 mL glacial acetic acid for 4.5 h. Solvent was evaporated. The residue was taken up in EtOAc and washed with sat'd aq NaHCO3, water, and brine. The organic phase was dried (MgSO4), filtered, and evaporated. The title compound was obtained as a solid and used without further purification (1.9 g, quant).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([CH2:16][C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.C=O.[C:42](=O)([O-])O.[Na+].C(OCC)(=O)C>CS(C)=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([C:16]([C:17]([O:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:18])=[CH2:42])[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(CC(=O)OC(c3ccccc3)c3ccccc3)c(F)cc2c1=O
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1OC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 1462.5 %

Procedure:
2.64 g of ethyl 1-cyclopropyl-7-diphenylmethoxycar-bonylmethyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quino-linecarboxylate was suspended in 20 ml of dimethylsulfoxide. Then 0.85 g of a 35% aqueous solution of formaldehyde and 21 mg of sodium hydrogencarbonate were added thereto and the mixture was stirred at 50° C. for 1.5 hours. To the reaction mixture, 100 ml of ethyl acetate and 50 ml of water were added and then the organic layer was collected. The organic layer thus collected was successively washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the obtained residue was dissolved in 25 ml of methylene chloride. Under ice-cooling, 0.57 g of methanesulfonyl chloride and 1.0 mg of triethylamine were successively dropped thereinto slowly and the resulting mixture was stirred at room temperature for 3 hours. 20 ml of water was added to the reaction mixture and the pH value of the mixture was regulated to 1 with 2N hydrochloric acid. Then the organic layer was collected, successively washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the oily product thus obtained was crystallized by adding ethanol and the crystals were collected by filtration. Thus 1.98 g of ethyl 1-cyclopropyl-7-(1-diphenylmethoxycarbonylvinyl)-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate was obtained (yield: 73.1%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:18])[CH:8]([OH:17])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:33])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:18])[CH:8]([O:17][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(O)C(=O)c1ccc(Cl)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)s1

Procedure:
To a mixture of ethyl 6-(5-chloro-2-thienyl)-5-hydroxy-6-oxohexanoate (21.6 g), pyridine (6.4 g) and tetrahydrofuran (100 ml) was added dropwise phenyl chlorocarbonate (12.7 g) with stirring under ice-cooling. After the resulting mixture was stirred at room temperature for 16 hours, the reaction mixture was concentrated, diluted with ethyl acetate (400 ml) and washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(5-chloro-2-thienyl)-6-oxo-5-phenoxycarbonyloxyhexanoate as a yellow oil (30.5 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH2:23]1[O:33][C:32]2[C:25](=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH:27]=O)[O:24]1.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:27][C:26]4[CH:29]=[CH:30][CH:31]=[C:32]5[O:33][CH2:23][O:24][C:25]=45)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1cccc2c1OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4cccc5c4OCO5)c23)c1

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 2,3-methylenedioxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(2,3-methylenedioxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 214-215° C.; HPLC: TRet (Grad5-40)=24.1.